The emergence of antibiotic-resistant bacteria has created an urgent demand for new antibacterial agents with novel mechanisms of action. Peptide deformylase (PDF), an essential enzyme involved in bacterial protein biosynthesis and maturation, is one of the few novel targets that are currently being pursued for antibacterial drug design.1-3 In bacteria, protein synthesis starts with an N-formylmethionine and as a result, all newly synthesized polypeptides carry a formylated N-terminus.4 PDF catalyzes the subsequent removal of the formyl group from the majority of those polypeptides, many of which undergo further N-terminal processing by methionine aminopeptidase to produce mature proteins. As an essential activity for survival,5-7 PDF is present in all eubacteria. On the other hand, protein synthesis in the eukaryotic cytoplasm does not involve N-terminal formylation and PDF apparently has no catalytic function in the mammalian mitochondrion.8 
PDF is a unique metallopeptidase, which utilizes a ferrous ion (Fe2+) to catalyze the amide bond hydrolysis.9,10 Due to sensitivity of the Fe2+ center to environmental oxygen and other reactive oxygen species, native PDF is extremely unstable and difficult to work with.11 However, substitution of Ni2+ or Co2+ for the Fe2+ ion renders the enzyme highly stable while retaining almost full catalytic activity and substrate specificity of the native enzyme. Consequently, most of the recent biochemical, structural, and inhibition studies were carried out with the metal-substituted forms.
Numerous PDF inhibitors have been reported in recent years; essentially all of them are metal chelators. On the basis of the chelator structure, they can be classified into three different types: the thiols,12-14 the hydroxamates,15-19 and the N-formylhydroxylamines or reverse hydroxamates.20,21 Many of the hydroxamate and reverse hydroxamate inhibitors exhibit excellent antibacterial activities in vitro and in animal studies. One of the reverse hydroxamates from British Biotech (BB-86398) is currently in phase I clinical trials. However, since most of these inhibitors still have significant peptide characteristics, there are some concerns about their selectivity (e.g., inhibition of matrix metalloproteases) and in vivo stability (e.g., proteolysis of the peptide bonds).